Irreversible EGFR TKIs Covalent tyrosine kinase inhibitors bind and inactivate EGFR kinase domain mutant dimers resistant to non-covalent tyrosine kinase inhibitors Authored: Orlic-Milacic, M, 2011-11-04 Covalent (irreversible) tyrosine kinase inhibitors (TKIs), pelitinib, WZ4002, HKI-272, canertinib and afatinib, form a covalent bond with the EGFR cysteine residue C397 and inhibit trans-autophosphorylation of mutants resistant to non-covalent TKIs. However, effective concentrations of covalent TKIs also inhibit wild type EGFR, resulting in severe side effects. Hence, covalent TKIs have not shown much promise as therapeutics. Edited: D'Eustachio, P, 2011-11-07 Edited: Jassal, B, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed20033049 Pubmed20966921 Reactome Database ID Release 431220611 Reactome, http://www.reactome.org ReactomeREACT_115744 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 has a Stoichiometric coefficient of 2 Resistant ligand-responsive EGFR mutants Resistant ligand-responsive EGFR mutants:Covalent EGFR TKIs